differential diagnosis and treatment of...

DIFFERENTIAL DIAGNOSIS AND TREATMENT OF ANTIPSYCHOTIC-RELATED MOVEMENT DISORDERS

Learning Objectives

• Apply evidence-based tools and strategies for the early identification and diagnosis of patients with tardive dyskinesia, akathisia, and other movement disorders

• Formulate appropriate, individualized treatment regimens for patients with tardive dyskinesia, akathisia, and other movement disorders associated with antipsychotic use

Extra-pyramidal Symptoms (EPS)

Movement Disorders: Akathisia

Akathisia: Subjective Symptoms

• Often extraordinarily difficult for the patient to describe, to some extent because there are few subjective states to which it can be compared

• Patients often use terms such as "anxiety" or "itching," although these do not really capture the essence of the condition

• Since many clinicians have never experienced it, there is often a lack of common ground in communicating the problem

Akathisia: Characteristic Distribution

Akathisia: Objective Signs• Objective sign is disordered movement

• Mild to moderate

• Predominantly lower extremities, usually from hips to ankles

• Shifting positions while standing or moving the feet around while sitting

• Increasing severity

• Can involve the entire body

• Nearly incessant writhing and rocking, accompanied by jumping around, running, and occasionally jumping out of a chair or a bed

• Isolated reports of akathisia occurring primarily in other body regions (such as suboccipital muscles) or in strange distributions, as in hemi-akathisia (affecting only one side of the body)

• Strange or unusual distributions of either subjective or objective components: consider another process influencing the clinical presentation, such as an infarction or an abscess

Dopaminergic Hypoactivity Causes Akathisia—Or Does It?

• Suggests direct DA link• Occurrence in Parkinson’s

disease• Similar disorders—RLS and

PLMD—are treated with DA agonists

• Most APs are potent antagonists at the D2 receptor

• Suggests it’s more complicated than that

• No established direct link between parkinsonism and akathisia

• Agents that cause least EPS can still cause akathisia

• SSRIs can cause akathisia• Indirect stimulation of 5HT2A

inhibits DA release

Antidepressant-Induced Akathisia

• There is growing awareness that akathisia can occur during treatment with antidepressants

• SSRIs have received the most reports of an association with akathisia

• TCAs and MAOIs have received fewer such reports

Hypothesized Mechanism of Akathisia:The Role of the Nucleus Accumbens

Cg1: cingulate gyrus, 1. OFC: orbitofrontal cortex. IL: infralimbic cortex. NAcbC: nucleus accumbens core. NAcbS: nucleus accumbens shell.

VTA: ventral tegmental area. LC: locus coeruleus.Stahl et al. CNS Spectrums 2011: www.neiglobal.com.

Akathisia: Incident Rates Across Indications in FDA Registration Trials

Agent Incident Rates of AkathisiaAripiprazole 10-13% monotherapy; 19-25% with lithium, divalproex, or antidepressants

Asenapine 4-11%Brexpiprazole 4-14% (MDD, dosed 1-3 mg/day); 4-7% (SZ, dosed 1-4 mg/day )Cariprazine 9-14% (SZ); 20% (3-6 mg/day) or 21% (9-12 mg/day) (BP-mania)Clozapine 3%Iloperidone 1-2%Lurasidone 6-22% (SZ); 4-11% (BP-depression)Olanzapine 3%Paliperidone 6-9%Quetiapine 1-4%Risperidone 5-9%Ziprasidone 8-10%

BP: bipolar depression. MDD: major depressive disorder. SZ: schizophrenia.Goldberg, Ernst. Managing the side effects of psychotropic medications. 2012.

Treatment Strategies for Akathisia

• Dosage reductions• Change to lower-risk agents if feasible• Withdrawal akathisia can occur; allow at least 6 weeks before judging effectiveness of

dose reduction/medication switch

• Benzodiazepines• Centrally-acting beta blockers

• Propranolol 30-90 mg/day• Betaxolol 10-20 mg/day

• Amantadine 100-200 mg bid• Gabapentin 1200 mg/day• Trazodone 100 mg/day• Mirtazapine 15 mg/day

• Anticholinergics (e.g., benztropine): no clear valueGoldberg et al. Managing the Side effects of psychotropic medications. 2012.

Movement Disorders: Tardive Dyskinesia

What is dyskinesia?

Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87;Aquino CC, Lang AE. Parkinsonism Related Disord 2014;20(suppl 1):S113-7.

RhythmicNonrhythmic

Non-suppressibleSuppressible

Tremors

AthetosisDystonia

Tics Chorea;Myoclonus

Dyskinesia Abnormal involuntary movements

Hyperkinetic movement disorder

SlowSustainedRapid

Types of Dyskinesia

Drug-induced• Levodopa-induced dyskinesia • Antipsychotic-induced dyskinesia• Dopamine receptor-blocking agents (DRBAs)

Vijayakumar D, Jankovic J. Drugs 2016;76(7):759-77; Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87.

What is tardive dyskinesia?

• Involuntary choreoathetoid movements usually associated with lower facial and distal extremity musculature (truncal movements also possible)

− Chorea: Quick, irregular, non-stereotyped movements− Athetosis: Slow, writhing, serpentine movements

• Not associated with direct sensory problems

• Of considerable clinical, medical, and legal concern because of potential persistence despite drug discontinuation

Dopamine supersensitivity?

= D2 antagonist

Nigrostriatal pathway

Blockade of D2 receptors in the nigrostriatal dopamine pathway

causes them to upregulateThis upregulation may lead

to tardive dyskinesia

Tardive dyskinesia

Stahl SM. Stahl’s essential psychopharmacology. 4th ed. 2013; Lohr JB et al. CNS Drugs 2003;17:47-62.

May contribute, but has lots of problems

Probably a better model for withdrawal-emergent dyskinesia

Other Mechanism(s) of Drug-Induced TD

• Abnormal synaptic plasticity−Chronic blockade of D2 receptors provokes maladaptive

plasticity in corticostriatal transmission

• Aberrant spine formation−D2 receptors on necks; glutamate receptors on heads

• Neuronal degeneration hypothesis− Oxidative and/or excitotoxic damage from free radicals− Considerable basic scientific evidence− May offer avenues for clinical treatment

Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87; Teo JT et al. Movement Disord 2012;27(10):1205-15; Aquino CC, Lang AE. Parkinsonism Related Disord 2014;20(suppl 1):S113-7; Stahl SM. CNS Spectr. 2017;22(6):427-434.

Tardive Dyskinesia: Delayed Onset

After 2 months of withdrawal of

depot agent

During exposureto DRBAs

After 1 month of withdrawal of

oral agent

After 3 months of cumulative

exposure to DRBAs

After 1 month of cumulative exposure

in older patients

Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87.

Symptoms should persist for longer than a month

Exposure to DRBAs

Tardive dyskinesia can occur in patients...

Diagnostic Criteria for TD

Schooler NR, Kane JM. Arch Gen Psychiatry. 1982;39:486-487;Glazer WM et al. J Clin Psychiatry; 1993;54:133-139. APA. DSM-IV. Washington DC: APA; 1994. APA. DSM-V. Washington DC: APA; 2013.

Source ExposureSeverity

threshold Duration MiscellaneousSchooler-Kane (1982) ≥3 months AIMS items: ≥3 in one

area or ≥2 in 2 areasPersistent ≥3 months

Dx of exclusion

Glazer et al. (1993) ≥3 months AIMS items: ≥3 total with at least one ≥2 in 1 area

Persistent ≥2 exams

Dx of exclusion

DSM-IV (1994)333.82

≥3 months≥1 month if ≥60 years

Involuntary movements ≥4 weeks Dx of exclusion

DSM-5 (2013)333.85 (G24.01)

At least few months

Involuntary movements ≥8 weeks

DSM = Diagnostic and Statistical Manual of Mental Disorders; Dx = diagnosis; APA = American Psychiatric Association

Mean TD Prevalence

Tardive Dyskinesia Prevalence in Second-Generation Antipsychotic Use

• TD prevalence is higher in patients treated with first-generation antipsychotics (FGAs)

• Recent meta-analysis comparison of TD prevalence in FGAs versus second-generation antipsychotics (SGAs) users

• However, SGAs still show risk of TD− 1/5 of patients treated with SGAs showed this

“rare” side effect

• In four studies, 7.2% prevalence with SGA reported in patients without prior FGA treatment

Carbon M et al. J Clin Psychiatry. 2017;78(3):e264-e278.

vs30.0%95% CI = 26.4%–33.8%

FGA Treatment

20.7%95% CI = 16.6%–25.4%

SGA Treatment

Mean TD Prevalence

95% CI = 16.6%–25.4%

SGA Treatment

20.7%

41 Studies (N = 11,493)Q = 9.17, P = 0.0024

TD rates significantly lower with SGA

treatment

Mean TD prevalence

SGA treatment

7.2%

Epidemiology of Tardive DyskinesiaApproximately 20–50% of patients receiving antipsychotics develop TD

Woerner et al. Am J Psychiatry 1998;155(11):1521-8; Correll CU et al. J Clin Psychiatry. 2017;78(8):1136-1147; Caroff SN et al. Neurol Clin. 2011;29(1):127-48, viii; Miller et al. Schizophr Res 2005;80(1):33-43; Nasrallah et al. Ann Clin Psychiatry

2006;18(1):57-62; Jeste et al. Arch Gen Psychiatry 1995;52(9):756-65; Jeste et al. Am J Psychiatry 2000;157(7):1150-5.

Risk Factors• Duration or cumulative antipsychotic exposure• Potency of antipsychotic• Older age is consistently found to be a risk factor for TD

• Geriatric patients: increased movement disorders, even in neuroleptic-naïve patients

− TD rates of 26–31% after 1 year of exposure to FGA− TD rates of 2.5% after 1 year of exposure to atypical antipsychotic

(risperidone, quetiapine)• Children: higher TD rates in patients taking haloperidol

Tardive Dyskinesia: Other Risk Factors• Early onset of psychosis• Presence of mood disorder• Acute EPS/akathisia• Treatment with anticholinergics• Negative symptoms, cognitive symptoms• Comorbid substance abuse• Sex: female, especially post-menopausal• Ethnicity?• Genetics tendency • 5% of medication-naïve schizophrenia patients exhibit spontaneous movementsCorrell CU et al. J Clin Psychiatry. 2017;78(8):1136-1147; Miller et al. Schizophr Res 2005;80(1):33-43; Nasrallah. Ann Clin Psychiatry 2006;18(1):57-62; Owens et al. Arch Gen Psychiatry 1982;39:452-61.

Abnormal Involuntary Movement Scale (AIMS)12-Item Clinician-Rated Scale to Assess Severity of Dyskinesias

• Regardless of DRBA choice and symptomatic profile, regular TD screening using the AIMS should be implemented routinely

• With FGA, examine for TD at least every 6 months• With second-generation antipsychotics SGA, examine for TD

every 12 months• Patients at high risk of EPS:

• examine for TD every 3 months with FGA• examine for TD every 6 months with SGA

Guy W. Abnormal Involuntary Movement Scale (117-AIMS), in ECDEU Assessment Manual for Psychopharmacology.1976: 534–7; Solmi M et al. J Neurol Sci. 2018;389:21-27.

Expected Course of Tardive Dyskinesia

Vinuela A et al. Tremor Other Hyperkinet Mov (N Y). 2014;4:282; Fernandez HH et al. Neurology. 2001;56(6):805-7; Glazer WM et al. Br J Psychiatry. 1990;157:585-92; Kang UJ et al. Mov Disord. 1986;1(3):193-208; Zutshi D et al. Other Hyperkinet Mov (N Y). 2014;4:266.

0%

20%

40%

60%

80%

100%

Medication discontinuation

~80% of patients

% P

atie

nts

with

TD

Time

• Long-term studies of the course of TD provide a wide range of remission rates (0–73%)1-4

−Most report remission rates below 25%

• After discontinuation of the causing DRBAs, the rate of remission is low

−Even with atypical antipsychotics, reversibility rates remain as low as only 20.5%5

Is tardive dyskinesia preventable?

• Inform patients of risk of developing TD before initiating treatment

• Use agents with less risk of TD−Risk increases with potency of D2 binding

• Patients should be monitored periodically for the development of TD

• Early recognition−Systematic evaluation including rating scales

Caroff SN et al. Current Psychiatry. 2011;10(10): 23-32; Bhidayasiri R et al. Neurology 2013;81:463-9; Vijayakumar D, Jankovic J. Drugs 2016;76(7):779-87.

Vesicular Monoamine Transporter (VMAT)

• Protein integrated into the membrane of synaptic vesicles of presynaptic neurons

• Transports monoamine neurotransmitters (DA, 5HT, NE, epinephrine, histamine) into vesicles

• Two forms: VMAT1 and VMAT2−VMAT1: expressed mainly in peripheral nervous system−VMAT2: expressed mainly in monoaminergic cells of the CNS

Kenney C, Jankovic J. Expert Rev Neurother 2006;6(1):7-17;Shen V et al. Tremor Other Hyperkinetic Movements 2013;3. doi:10.7916/D8BK1B2D;

Waln O, Jankovic J. Tremor Other Hyperkinetic Movements 2013;3. doi:10.7916/D88P5Z71.

VMAT2 Inhibition in Tardive Dyskinesia

tardive dyskinesia

psychosis

Tetrabenazine: Efficacy and Safety

• Level C recommendation from American Academy of Neurology 2013 (AAN Guidelines)4,6

• Common side effects associated with TBZ include:5

−Drowsiness−Parkinsonism−Akathisia−Depression

Ondo W et al. Am J Psychiatry 1999;156:1279-81; Kenney C, Jankovic J. Expert Rev Neurother 2006;6(1):7-17; Guay D. Am J Geriatr Pharmacother 2010;8(4):331-73; Bhidayasiri R et al. Neurology 2013;81:463-9; Kenney C et al. Movement

Disord 2007;22(2):193-7; Bhidayasiri R et al. J Neurol Sci. 2018;389:67-75.

• TBZ has been shown to reduce TD symptoms by 54%1

−Approved in US in 2008 for Huntington's disease

• Studies have shown improvement of symptoms in 70–71% of patients treated with TBZ 2,3

Tetrabenzine Historical ApprovalCountryUnited States Huntington’s chorea 2008Netherlands Huntington’s chorea 2007Germany Huntington’s chorea and tardive dyskinesia 2007Italy Organic movement disorder and tardive dyskinesia 2007France Huntington’s chorea and hemiballismus 2005Israel Organic movement disorder and tardive dyskinesia 2005Portugal Organic movement disorder and tardive dyskinesia 2003Canada Organic movement disorder and tardive dyskinesia 1995Denmark Hyperkinesias 1980Australia Organic movement disorder and tardive dyskinesia 1979New Zealand Organic movement disorder and tardive dyskinesia 1973Ireland Organic movement disorder (tardive refused) 1971UK Organic movement disorder and tardive dyskinesia 1971

O

ON

O

H

Tetrabenazine ()-1

O

ON

O

H

(+)-1(3R,11bR)-TBZ

(-)-1(3S,11bS)-TBZ

O

ON

O

H

Rapidly converted to dihydrotetrabenazine α, β enantiomers in a

ratio of 1:1

Yao Z et al. Eur J Med Chem 2011;46(5):1841-8.

Metabolites are metabolized via CYP2D6

Metabolism of Tetrabenazine

Requires mandatory CYP2D6 genotyping for doses >50 mg/day

O

O N

O

H

TBZ Enantiomers (±)-1

O

ON

OH

H

O

ON

OH

H

O

ON

OH

H

O

ON

OH

H

(2R,3R,11bR)-DHTBZ (+)-2 (2S,3S,11bS)-DHTBZ (-)-2 (2S,3R,11bR)-DHTBZ (+)-3 (2R,3S,11bS)-DHTBZ (-)-3

(−)-𝜶𝜶-DHTBZ (+)-𝜷𝜷-DHTBZ (−)-𝜷𝜷-DHTBZ(+)-𝜶𝜶-DHTBZ

Evidence Suggests That Binding of the TBZ Metabolites to VMAT2 is Stereospecific

TBZ: tetrabenazine DHTZB: dihydrotetrabenazine

Ki: 3.96

Yao et al. Eur J Med Chem 2011;46(5):1841-8; Kilbourn et al. Chirality 1997;9(1):59-62.

Ki: 23,700 Ki: 13.4 Ki: 2,460

DHTBZ metabolitesHighest binding

affinity for VMAT2

VMAT2 binding affinity

Valbenazine• Designed to deliver metabolite in a controlled fashion

Müller T. Expert Opinion Investig Drugs 2015;24(6):737-42; O'Brien et al. Movement Disord 2015;30(12):1681-7; Skor H et al. Drugs R D. 2017; 2017 Sep;17(3):449-459.

O

ON

OH

H

(+)-𝜶𝜶-DHTBZ

O

N

H

O

ON HH

O

Valbenazine

• Limited off-target receptor binding• FDA approved for the treatment of TD, April 2017

- Initial dose 40 mg/day, after 1 week increase dose to 80 mg/day- No need for CYP2D6 genotyping

Valbenazine: Selective VMAT2 InhibitorCumulative proportion of responders during 6-week, double-blind, phase II trial

Response: at least 50% improvement in AIMS placebo n=44, NBI-98854 n=45

O'Brien et al. Movement Disord 2015;30(12):1681-7.

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

0 2 4 6

Placebo

AIMS score (least squares [LS] mean change from baseline to week 6, MMRM):

Valbenazine 40 mg-1.9 vs. -0.1 placebo; p<0.05; effect size, d=0.52

Valbenazine 80 mg -3.2 vs. -0.1 placebo; p<0.001; effect size, d=0.90

Change from baseline in the severity of TD symptoms assessed by the Abnormal Involuntary Movement Scale (AIMS) through week 6

AIMS at week 6 for the valbenazine 80 mg dose was reduced 3.1 points more than placebo (p<0.001)Hauser RA et al. Am J Psychiatry. 2017;174(5):476-484.

Valbenazine EfficacyKINECT 3 AIMS Outcomes at Week 6

Time (weeks)

LS m

ean

chan

ge (S

EM)

ValbenazineSafety and Tolerability

• PK profile permits once-daily dosing• Psychiatric status remained stable • Improved TD regardless of the use or type of concomitant AP• Somnolence is the most common treatment-related AE

- Valbenazine (all doses), 10.9%; placebo, 4.2%- May be due to depletion of monoamines in people with higher

plasma levels of valbenazine

O'Brien et al. Movement Disord 2015;30:1681-7; Hauser RA et al. Neurology 2016;86(16)(suppl PL02.003); Hauser RA et al. Am J Psychiatry. 2017;174(5):476-484; Citrome L. Int J Clin Pract. 2017;e12964.

Valbenazine Appears Safe and Well-Tolerated Long-Term

• Data pooled from three long-term studies with valbenazine (up to 48 weeks) in adults with TD

• 66.5% of patients experienced treatment-emergent adverse events (TEAEs), but only about 14.7% discontinued the drug due to AEs

Josiassen RC et al. Poster presented at: American Psychiatric Association (APA) 2017 Annual Meeting; May 22, 2017; San Diego, CA.

• Patients with mood disorders:- headache (12.4%)- urinary tract infection (10.7%)- somnolence (9.1%)

• Patients with schizophrenia:- urinary tract infection (6.1%)- headache (5.8%)- somnolence (5.2%)

Tetrabenazine

• Deuteration is the replacing of hydrogen atoms with deuterium on a compound• Deuteration is the replacing of hydrogen atoms with deuterium on a compound• Deuteration is the replacing of hydrogen atoms with deuterium on a compound

D3C

D3C

H3C

H3C

H3C

H3C

Deutetrabenazine

DeutetrabenazineTetrabenazineO

- No change in shape, size, charge, or target pharmacology of small molecules

- Chemical bond C-D is 8x stronger

- Prolongs half-life and improved PK

• Deutetrabenazine is a selective VMAT2 inhibitor

Fernandez HH et al. Neurology. 2017;88(21):2003-2010; Anderson et al. Poster presented at: American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA; NEI Prescribe App, 2017.

N

H

O

O

FDA Approved for Tardive Dyskinesia on August 30, 2017- Initial dose 12 mg/day in two divided doses- Titrate at weekly intervals by 6 mg/day based on reduction of tardive dyskinesia and tolerability- Maximum recommended daily dosage of 48 mg (24 mg twice daily)- No need to CYP2D6 genotyping

Pharmacokinetics of Deutetrabenazine

70

60

50

40

30

20

10

0

Plas

ma

conc

entra

tion

(ng/

mL)

Time post dose (hours)

0 6 12 18 24

Deutetrabenazine, 15 mg, fed

Deutetrabenazine, 15 mg, fasted

Tetrabenazine, 25 mg, fasted

Mean plasma concentrationTOTAL alpha + beta (n=24-25)

Anderson et al. Poster presented at: American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

Deutetrabenazine: Phase III Randomized ARM-TD Dose-Finding Trial

0

-1

-2

-3

-4Baseline 2 4 6 9 12

Weeks

Mea

n ch

ange

in A

IMS

scor

e

*

**

Deutetrabenazine

Placebo group (n=59)Decrease in mean AIMS: 1.6 (SE=0.46)

Deutetrabenazine group(n=58) Decrease in mean AIMS:3.0 (SE=0.45)

p=0.019

At Week 12

Mean change in AIMS score

AEs: somnolence, headache

Double-blind, placebo-controlled, parallel-group study

Placebo

AIMS: Abnormal Involuntary Movement Scale.

Fernandez HH et al. Neurology. 2017;88(21):2003-2010.

Deutetrabenazine: Phase III Randomized AIM-TD Fixed-Dose Trial

At Week 12

Anderson KE et al. Lancet Psychiatry. 2017;4(8):595-604.

AIMS: Abnormal Involuntary Movement Scale. 0

-1

-2

-3

-40 2 4 6 8 10 12

Week

Leas

t-squ

ares

mea

n ch

ange

(poi

nts)

Placebo group mean AIMS: -1.4 points (SE=0.41)

Deutetrabenazine 12 mg/dmean AIMS: −2.1 points (SE 0.42)



*

**

***

****

* p=0·006 for 24 mg/day and 0·032 for 36 mg/day** p=0·003 for 24 mg/day and 0·018 for 36 mg/day*** p=0·012 for 24 mg/day and 0·008 for 36 mg/day**** p=0·003 for 24 mg/day and 0·001 for 36 mg/day

Deutetrabenazine: Intention-to-Treat AnalysisSignificant Reductions in Abnormal Involuntary Movements

• CGIC at week 12• Treatment success was

defined as a rating of “much improved” or “very much improved” on the CGIC

• Deutetrabenazine at doses of 24 mg/day and 36 mg/day were efficacious and well tolerated

Deutetrabenazine36 mg/day

(n=55)


(n=49)


(n=60)

55

CG

IC tr

eatm

ent s

ucce

ss (%

)

50

45

40

35

30

25

20

15

10

5

0

Clinical global impression of change (CGIC)

26% 28%

49%44%

Placebo (n=58)

***

*p = 0.014**p = 0.059

Anderson KE et al. Lancet Psychiatry. 2017;4(8):595-604.

Three Ways to Block VMAT2 With Three Benazines

1. Tetrabenazine – not approved in the United States

2. Valbenazine – FDA approved for the treatment of TD, April 2017

3. Deutetrabenazine – FDA approved for the treatment of TD, August 2017

• No head-to-head studies, all share the same fundamental mechanism

• Major differences are in pharmacokinetics, but differences in efficacy or safety are not yet well established

• Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A)

Bhidayasiri R et al. J Neurol Sci. 2018;389:67-75.

American Academy of Neurology (AAN): Updated Recommendations for Treatment of Tardive Syndrome

Bhidayasiri R et al. J Neurol Sci. 2018;389:67-75.

Level Amust be recommended

as treatment

• Deutetrabenazine• Valbenazine

Level A Level Bmust be recommended

as treatmentshould be considered as

treatment


• Clonazepam• Ginkgo biloba

Level A Level B Level Cmust be recommended


treatmentmight be considered as

treatment



• Amantadine• Tetrabenazine• Pallidal deep

brain stimulation (intractable TD)

Level A Level B Level C Level Umust be recommended


treatmentmight be considered as

treatment insufficient evidence to

support or refute



• Amantadine• Tetrabenazine• Pallidal deep

brain stimulation (intractable TD)

• Withdrawing causative agents

• Switching from typical to atypical DRBA

Movement Disorders: Drug-Induced Parkinson’s (DIP)

Label Change for VMAT-2• Valbenazine – section 5.3• Deutetrabenazine – section 5.5

Ways you can see co-existence of DIP and TD

Exposure to DRBAs (Co-

existent)

VMAT-2 Mechanism of

Action)

Co-existent but unrecognized

Drug-Induced Parkinson’s (DIP)

• DIP is the most common movement disorder induced by drugs that affect dopamine receptors (e.g., DRBAs)

• Risk factors: age, female gender

• Genetic risk factors: genes associated with GABA receptor-signaling pathway are involved in neuroleptic-induced TD in schizophrenic patients

Shin and Chung. J Clin Neurol. 2012;8:15-21.

Which drugs are most commonly associated with high risk for DIP?

Changes to the Brain Due to Blockade of D2 Receptors by DRBAs

Dopamine Transporter Scans May Be Helpful in Diagnosing DIP

DIP Trajectories/Outcomes

Prognosis Outcome

Type I Full and long-lasting recovery from DIP with no subsequent developed parkinsonism

Type II Persistence but not progression of parkinsonism

Type III Persistence and eventual worsening of parkinsonism

Type IV Full remission of parkinsonism but later reappearance after discontinuation of the drug

Treatment for DIP

Stop taking the offending drug

Patient Type Treatment

Patients who cannot stop taking antipsychotics for psychiatric reasons

Switch to atypical antipsychotics with lower risk of EPS

Patients who have been prescribed DA antagonists due to GI disturbances

Stop taking offending drug immediately

AnticholinergicsTrihexyphenidyl

BenztropineAmantadine

Levodopa / Dopamine AgonistsDBS ?

Felker BL et al. Am J Psych 2003; 160(1):174–17.

How do you manage TD patients on VMAT-2 who also have DIP?

Summary• Differentiating among various extrapyramidal symptoms (EPS) is

important for accurate diagnosis of movement disorders• Agents associated with the least EPS risk can still cause

akathisia• Tardive dyskinesia (TD) remains a serious risk of APs and other

DRBAs• Drug-induced parkinsonism (DIP) is the most common movement

disorder induced by DRBAs

• Awareness of effective treatment strategies available for akathisia, TD, and DIP enhances appropriate treatment of movement disorders

differential diagnosis and treatment of...

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